Risk Phenotypes, Comorbidities, Pharmacotherapy, and Electroconvulsive Therapy (ECT) in a Cohort with Difficult-to-Treat Depression in Comparison to an Unmedicated Control Group.

BACKGROUND: Approximately 15-25% of depressed patients suffer from difficult-to-treat depression (DTD). Patients with DTD require a thorough examination to avoid the oversight of treatable (psychiatric/somatic) comorbidities or (pseudo-)resistance to antidepressant drugs (ADs). Polymorphisms of the cytochrome P450 (CYP) enzymes 2D6 and 2C19, which play a major role in the metabolism of ADs, may contribute to resistance to ADs. Patients with DTD might benefit from electroconvulsive therapy (ECT). METHODS: We enrolled 109 patients with DTD and 29 untreated depressed controls (UDC). We assessed risk phenotypes, comorbidities, and treatment, including ECT. We also performed pharmacokinetic analyses of CYP2D6 and CYP2C19. RESULTS: DTD patients significantly more often suffered from comorbid psychiatric diseases, especially ICD-10: F40-F48 (DTD:40.4%, UDC:17.2%, OR 11.87, p=0.011) than UDC patients. DTD patients receiving ECT were more likely to achieve remission (37.7% vs. 11.8%, OR=3.96, p=0.023). Treatment with ADs did not differ between remitters and non-remitters. No significant differences were observed in the distribution of CYP2D6 and CYP2C19 variants between both groups. CONCLUSION: Patients with DTD appear to experience comorbid neurotic stress and somatoform disorders (ICD-10: F40 - F48) more frequently. Therefore, a comprehensive differential diagnosis is crucial when patients do not respond sufficiently to antidepressant medication. Genotyping CYP2D6 and CYP2C19 should be considered.

Validation of the predictive value of BDNF -87 methylation for antidepressant treatment success in severely depressed patients-a randomized rater-blinded trial.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is essential for antidepressant treatment of major depressive disorder (MDD). Our repeated studies suggest that DNA methylation of a specific CpG site in the promoter region of exon IV of the BDNF gene (CpG -87) might be predictive of the efficacy of monoaminergic antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and others. This trial aims to evaluate whether knowing the biomarker is non-inferior to treatment-as-usual (TAU) regarding remission rates while exhibiting significantly fewer adverse events (AE). METHODS: The BDNF trial is a prospective, randomized, rater-blinded diagnostic study conducted at five university hospitals in Germany. The study's main hypothesis is that {1} knowing the methylation status of CpG -87 is non-inferior to not knowing it with respect to the remission rate while it significantly reduces the AE rate in patients experiencing at least one AE. The baseline assessment will occur upon hospitalization and a follow-up assessment on day 49 (± 3). A telephone follow-up will be conducted on day 70 (± 3). A total of 256 patients will be recruited, and methylation will be evaluated in all participants. They will be randomly assigned to either the marker or the TAU group. In the marker group, the methylation results will be shared with both the patient and their treating physician. In the TAU group, neither the patients nor their treating physicians will receive the marker status. The primary endpoints include the rate of patients achieving remission on day 49 (± 3), defined as a score of ≤ 10 on the Hamilton Depression Rating Scale (HDRS-24), and the occurrence of AE. ETHICS AND DISSEMINATION: The trial protocol has received approval from the Institutional Review Boards at the five participating universities. This trial holds significance in generating valuable data on a predictive biomarker for antidepressant treatment in patients with MDD. The findings will be shared with study participants, disseminated through professional society meetings, and published in peer-reviewed journals. TRIAL REGISTRATION: German Clinical Trial Register DRKS00032503. Registered on 17 August 2023.

Comparative Analysis of SARS-CoV-2 Antibody Responses across Global and Lesser-Studied Vaccines.

Few data are available on antibody response for some SARS-CoV-2 vaccines, and there is a lack of ability to compare vaccine responses in the same population. This cross-sectional study conducted in Nicaragua examines the SARS-CoV-2 antibody responses in individuals, previously exposed to high infection rates who have received various vaccines. The vaccines under comparison include well-known ones like Pfizer (BNT162b2) and AstraZeneca (ChAdOx1-S), alongside less-studied vaccines including Soberana (Soberana 02), Abdala (CIGB-66), and Sputnik V/Sputnik Light. Overall, 3195 individuals participated, with 2862 vaccinated and 333 unvaccinated. We found that 95% of the unvaccinated were seropositive, with much lower titers than the vaccinated. Among the vaccinated, we found that Soberana recipients mounted the highest anti-spike response (mean difference (MD) = 36,498.8 [20,312.2, 52,685.5]), followed by Abdala (MD = 25,889.9 [10,884.1, 40,895.7]), BNT162b2 (MD = 12,967.2 [7543.7, 18,390.8]) and Sputnik with AstraZeneca as the reference group, adjusting for age, sex, vaccine status, days after last dose, and self-reported COVID-19. In addition, we found that subjects with complete vaccination series had higher antibody magnitude than those with incomplete series. Overall, we found no evidence of waning in the antibody magnitude across vaccines. Our study supports the conclusion that populations with high infection rates still benefit substantially from vaccination.

Reduction in Long COVID Symptoms and Symptom Severity in Vaccinated Compared to Unvaccinated Adults.

Background: The impact of vaccination prior to infection on postacute sequelae of coronavirus disease 2019 (COVID-19, PASC), also known as long COVID, remains unclear. Here we assess the protective effect of vaccination on long COVID in a community-based setting. Methods: The Immunity Associated with SARS-CoV-2 (IASO) study is an ongoing prospective cohort of working adults that began in October 2020. Participants are actively followed for severe acute respiratory syndrome coronavirus 2 infection. We compared the prevalence of symptoms and symptom severity in vaccinated compared to unvaccinated cases. Our primary definition of long COVID was the presence of symptoms at 90 days postinfection; 30 days postinfection was also examined. Results: Overall, by 90 days postinfection, 13% of cases had long COVID, with 27% of unvaccinated cases and 8% of vaccinated cases reporting long COVID (relative risk [RR], 0.31 [95% confidence interval {CI}, .22-.42]). Vaccination was also associated with significantly lower average severity scores at all timepoints (eg, relative severity at 90 days postinfection: -2.70 [95% CI, -1.68 to -3.73]). In the pre-Omicron era, 28% of unvaccinated cases and 18% of vaccinated cases reported long COVID (P = .07), and vaccinated cases reported less severe symptoms including less difficulty breathing (P = .01; 90-day RR, 0.07). Conclusions: Vaccinated cases had lower prevalence of long COVID and reduced symptom severity.

The significance of cerebrospinal fluid analysis in the differential diagnosis of 564 psychiatric patients: Multiple sclerosis is more common than autoimmune-encephalitis.

The analysis of cerebrospinal fluid (CSF) is an essential tool for the differential diagnosis of psychiatric disorders caused by autoimmune inflammation or infections. Clear guidelines for CSF analysis are limited and mainly available for schizophrenia and dementia. Thus, insights into CSF changes in psychiatric patients largely derive from research. We analyzed the clinical and CSF data of 564 psychiatric patients without pre-existing neurological diagnoses from March 1998 to April 2020. Primary aim was to detect previously undiagnosed neurological conditions as underlying cause for the psychiatric disorder. Following CSF analysis, 8 % of patients (47/564) were diagnosed with a neurological disorder. This was the case in 12.0 % (23/193) of patients with affective disorders, 7.2 % (19/262) of patients with schizophrenia, and 4.0 % (23/193) of patients with anxiety disorders. The predominant new diagnoses were multiple sclerosis (19/47) and autoimmune encephalitis (10/47). Abnormal CSF findings without any implications for further treatment were detected in 17.0 % (94/564) of patients. Our data indicates that CSF analysis in patients suffering from psychiatric disorders may uncover underlying organic causes, most commonly multiple sclerosis and autoimmune encephalitis. Our findings imply that the incorporation of CSF analysis in routine psychiatric assessments is potentially beneficial.

Clinical and sociodemographic predictors of inpatient admission after presentation in a psychiatric emergency room: an observational study.

BACKGROUND: The admission decision after presentation in the psychiatric emergency room (PER) has potentially far-reaching consequences for the patient and the community. In a short amount of time, information must be collected and evaluated for a well-founded admission decision. The present study aimed to identify risk factors associated with inpatient psychiatric admission (IPA) after previous emergency presentation to the PER. METHODS: Electronic patient records for all patients presenting in the PER of Hannover Medical School (MHH) in the year 2022 were retrospectively examined (n = 2580). Out of these, 2387 were included in this study. Two multivariate binary logistic regression analyses were performed to identify risk factors for IPA within sociodemographic, circumstantial and clinical variables. RESULTS: 1300 (54.5%) consultations resulted in IPA. The most significant sociodemographic and circumstantial risk factors for IPA were found to be suicide attempt (depending on method: OR 9.1-17.4), aggressive behavior towards people prior to presentation (OR 2.9, 95% CI 1.7-4.8), previous psychiatric treatment (OR 1.8, 95% CI 1.4-2.3) and transfer from another hospital or medical discipline of MHH as means of presentation (OR 6.3, 95% CI 3.0-13.0). Among psychopathological aspects, suicidal ideation (OR 3.8, 95% CI 2.9-4.9), suicidal intent (OR 116.0, 95% CI 15.9-844.8), disturbance of orientation (OR 3.7, 95% CI 2.5-5.3), delusions (OR 2.3, 95% CI 1.6-3.1), visual hallucinations (OR 2.9, 95% CI 1.6-5.1), hopelessness/despair (OR 2.4, 95% CI 1.7-3.2) and inhibition of drive (OR 1.6, 95% CI 1.3-2.1) were significantly associated with IPA. CONCLUSIONS: The admission decision is a complex process influenced by a multitude of sociodemographic, circumstantial and clinical factors. A deeper understanding of the decision-making process can be used to improve patient care and facilitate the evaluation process in the PER.

Increased influenza severity in children in the wake of SARS-CoV-2.

The SARS-CoV-2 pandemic and subsequent interruption of influenza circulation has lowered population immunity to influenza, especially among children with few prepandemic exposures. Using data from a prospective pediatric cohort study based in Managua, Nicaragua, we compared the incidence and severity of influenza A/H3N2 and influenza B/Victoria between 2022 and two prepandemic seasons. We found a higher incidence of A/H3N2 in older children in 2022 compared with pre-2020 and a higher proportion of severe influenza in 2022, primarily among children aged 0-4, suggesting an influence of the SARS-CoV-2 pandemic on influenza incidence and severity in children.

Alzheimer's disease biomarkers in cerebrospinal fluid are stable with the Elecsys immunoassay to most pre-analytical influencing factors except freezing at -80 °C.

BACKGROUND: Alzheimer´s disease is considered a neurodegenerative disease and is diagnosed by exclusion, while the detection of specific cerebrospinal fluid (CSF) biomarkers, namely amyloid-beta (Aß) peptides Aß1-42 (Aß42), phospho-tau (181P; P-tau), and total-tau (T-tau), has been shown to improve diagnostic accuracy. Recently, a new generation of sample tubes (Sarstedt false-bottom tubes) for the Elecsys CSF immunoassay for the determination of Alzheimer´s disease biomarkers in CSF was introduced, promising better measurability. However, the pre-analytic influencing factors have not yet been sufficiently investigated. METHODS: In 29 patients without Alzheimer's disease diagnosis, CSF concentrations of Aß42, P-tau and T-tau were examined in native CSF and after different influencing interventions using the Elecsys immunoassay test method. The following influencing factors were analyzed: contamination with blood (10,000 and 20,000 erythrocytes/µl CSF), 14-day storage at 4 °C, blood contamination of CSF and 14-day storage at 4 °C, 14-day freezing at -80 °C in Sarstedt tubes or glass vials, 3-month intermediate storage at -80 °C in glass vials. RESULTS: Both storage at -80 °C for 14 days in Sarstedt false-bottom tubes and in glass vials and storage at -80 °C for 3 months in glass vials resulted in significant decreases in Aß42 (13% after 14 days in Sarstedt and 22% in glass vials, 42% after 3 months in glass vials), P-tau (9% after 14 days in Sarstedt and 13% in glass vials, 12% after 3 months in glass vials) and T-tau (12% after 14 days in Sarstedt and 19% in glass vials, 20% after 3 months in glass vials) concentrations in CSF. No significant differences were found for the other pre-analytical influencing factors. CONCLUSIONS: Measurements of the concentrations of Aß42, P-tau, and T-tau in CSF with use of the Elecsys immunoassay are robust to the pre-analytical influencing factors of blood contamination and duration of storage. Freezing at -80 °C results in significant reduction of biomarker concentrations regardless of the storage tube and must be considered in retrospective analysis.

Bifrontal electroconvulsive therapy leads to improvement of cerebral glucose hypometabolism in frontotemporal dementia with comorbid psychotic depression - a case report.

BACKGROUND: Differentiating depression and dementia in elderly patients represents a major clinical challenge for psychiatrists. Pharmacological and non-pharmacological treatment options for both conditions are often used cautiously due to fear of adverse effects. If a clinically indicated therapy is not initiated due to fear of adverse effects, the quality of life of affected patients may significantly be reduced. CASE PRESENTATION: Here, we describe the case of a 65-year-old woman who presented to the department of psychiatry of a university hospital with depressed mood, pronounced anxiety, and nihilistic thoughts. While several pharmacological treatments remained without clinical response, further behavioral observation in conjunction with 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) revealed the diagnosis of frontotemporal dementia (FTD). To counter the pharmacological treatment resistance of psychotic depression, we decided to perform electroconvulsive therapy (ECT). Remarkably, ten sessions of ECT yielded an almost complete remission of depressive symptoms. In addition, the patient's delusional ideas disappeared. A follow-up 18F-FDG PET/CT after the ECT series still showed a frontally and parieto-temporally accentuated hypometabolism, albeit with a clear regression compared to the previous image. The follow-up 18F-FDG PET/CT thus corroborated the diagnosis of FTD, while on the other hand it demonstrated the success of ECT. CONCLUSIONS: In this case, ECT was a beneficial treatment option for depressive symptoms in FTD. Also, 18F-FDG PET/CT should be discussed as a valuable tool in differentiating depression and dementia and as an indicator of treatment response.

[Clinical use of psychotropic drugs: A look at antipsychotic drugs]. / Psychopharmaka in der Praxis: Ein Blick auf Antipsychotika.

Antipsychotic drugs were originally developed to treat the positive symptoms of schizophrenia (e.g., delusions, hallucinations). Nowadays, antipsychotic drugs are also commonly used in the treatment of geriatric patients, especially those suffering from dementia. When treating behavioural symptoms of dementia, the use of antipsychotic drugs should not be first choice and when they do present the best treatment option, they should not be used long-term. Patients suffering from schizophrenia, on the other hand, may require long-term treatment with antipsychotic drugs in order to avoid relapse. In the following, the use of antipsychotic drugs in the treatment of schizophrenia and behavioural symptoms in dementia according to the respective treatment guidelines will be explained. In addition, the pharmacological receptor profiles of frequently used antipsychotic drugs (e.g., risperidone, haloperidol, quetiapine, aripiprazole) are presented and the expected adverse drug reactions, such as extrapyramidal symptoms and hyperprolactinemia, are explained. Treatment options of the most common adverse drug reactions associated with antipsychotic drugs are also presented.

Increased Influenza Severity in Children in the Wake of SARS-CoV-2.

The SARS-CoV-2 pandemic and subsequent interruption of influenza circulation has lowered population immunity to influenza, especially among children with few pre-pandemic exposures. We compared the incidence and severity of influenza A/H3N2 and influenza B/Victoria between 2022 and two pre-pandemic seasons and found an increased frequency of severe influenza in 2022.

DNA Methylation of POMC and NR3C1-1F and Its Implication in Major Depressive Disorder and Electroconvulsive Therapy.

INTRODUCTION: Precision medicine in psychiatry is still in its infancy. To establish patient-tailored treatment, adequate indicators predicting treatment response are required. Electroconvulsive therapy (ECT) is considered one of the most effective options for pharmacoresistant major depressive disorder (MDD), yet remission rates were reported to be below 50%. METHODS: Since epigenetics of the stress response system seem to play a role in MDD, we analyzed the DNA methylation (DNAm) of genes encoding the glucocorticoid receptor (NR3C1) and proopiomelanocortin (POMC) through Sanger Sequencing. For analysis, blood was taken before and after the first and last ECT from MDD patients (n=31), unmedicated depressed controls (UDC; n=19, baseline), and healthy controls (HC; n=20, baseline). RESULTS: Baseline DNAm in NR3C1 was significantly lower in UDCs compared to both other groups (UDC: 0.014(±0.002), ECT: 0.031(±0.001), HC: 0.024(±0.002); p<0.001), whereas regarding POMC, ECT patients had the highest DNAm levels (ECT: 0.252(±0.013), UDC: 0.156(±0.015), HC: 0.162(±0.014); p<0.001). NR3C1m and POMCm decreased after the first ECT (NR3C1: p<0.001; POMC: p=0.001), and responders were less methylated compared to non-responders in NR3C1(p<0.001). DISCUSSION: Our findings indicate that both genes might play a role in the chronification of depression and NR3C1 may be relevant for ECT response prediction.

Neurological soft signs are increased in major depressive disorder irrespective of treatment.

The significance of neurological soft signs (NSS) in major depressive disorder (MDD) remains unclear and the stability of NSS in relation to antidepressant treatment has never been investigated. We hypothesized that NSS are relatively stable trait markers of MDD. We thus predicted that patients show more NSS than healthy controls, irrespective of illness duration and antidepressant treatment. To test this hypothesis, NSS were assessed in chronically depressed, medicated MDD patients before (n = 23) and after (n = 18) a series of electroconvulsive therapy (ECT). In addition, NSS were assessed once in acutely depressed, unmedicated MDD patients (n = 16) and healthy controls (n = 20). We found that both chronically depressed, medicated MDD patients and acutely depressed, unmedicated MDD patients showed more NSS than healthy controls. The degree of NSS in both patient groups did not differ. Importantly, we found no change in NSS after on average eleven sessions of ECT. Thus, the manifestation of NSS in MDD seems to be independent of illness duration and pharmacological and electroconvulsive antidepressant treatment. From a clinical perspective, our findings corroborate the neurological safety of ECT.

SARS-CoV-2 infection-induced immunity and the duration of viral shedding: Results from a Nicaraguan household cohort study.

BACKGROUND: Much of the world's population has been infected with SARS-CoV-2. Thus, immunity from prior infection will play a critical role in future SARS-CoV-2 transmission. We investigated the impact of infection-induced immunity on viral shedding duration and viral load. METHODS: We conducted a household cohort study in Managua, Nicaragua, with an embedded transmission study that closely monitors participants regardless of symptoms. Real-time reverse-transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assays (ELISAs) were used to measure infections and seropositivity, respectively. Blood samples were collected twice annually and surrounding household intensive monitoring periods. We used accelerated failure time models to compare shedding times. Participants vaccinated ≥14 days prior to infection were excluded from primary analyses. RESULTS: There were 600 RT-PCR-confirmed SARS-CoV-2 infections in unvaccinated participants between May 1, 2020, and March 10, 2022, with prior ELISA data. Prior infection was associated with 48% shorter shedding times (event time ratio [ETR] 0.52, 95% CI: 0.39-0.69, mean shedding: 13.7 vs. 26.4 days). A fourfold higher anti-SARS-CoV-2 spike titer was associated with 17% shorter shedding (ETR 0.83, 95% CI: 0.78-0.90). Similarly, maximum viral loads (lowest cycle threshold [CT]) were lower for previously infected individuals (mean CT 29.8 vs. 28.0, p = 4.02 × 10-3 ), for adults and children ≥10 years, but not for children 0-9 years; there was little difference in CT levels for previously infected versus naïve adults aged above 60 years. CONCLUSIONS: Prior infection-induced immunity was associated with shorter viral shedding and lower viral loads, which may be important in the transition from pandemic to endemicity.

The Nicaraguan Pediatric Influenza Cohort Study, 2011-2019: Influenza Incidence, Seasonality, and Transmission.

BACKGROUND: Children account for a large portion of global influenza burden and transmission, and a better understanding of influenza in children is needed to improve prevention and control strategies. METHODS: To examine the incidence and transmission of influenza we conducted a prospective community-based study of children aged 0-14 years in Managua, Nicaragua, between 2011 and 2019. Participants were provided with medical care through study physicians and symptomatic influenza was confirmed by reverse-transcription polymerase chain reaction (RT-PCR). Wavelet analyses were used to examine seasonality. Generalized growth models (GGMs) were used to estimate effective reproduction numbers. RESULTS: From 2011 to 2019, 3016 children participated, with an average of ∼1800 participants per year and median follow-up time of 5 years per child, and 48.3% of the cohort in 2019 had been enrolled their entire lives. The overall incidence rates per 100 person-years were 14.5 symptomatic influenza cases (95% confidence interval [CI]: 13.9-15.1) and 1.0 influenza-associated acute lower respiratory infection (ALRI) case (95% CI: .8-1.1). Symptomatic influenza incidence peaked at age 9-11 months. Infants born during peak influenza circulation had lower incidence in the first year of their lives. The mean effective reproduction number was 1.2 (range 1.02-1.49), and we observed significant annual patterns for influenza and influenza A, and a 2.5-year period for influenza B. CONCLUSIONS: This study provides important information for understanding influenza epidemiology and informing influenza vaccine policy. These results will aid in informing strategies to reduce the burden of influenza.

The Spectrum of Influenza in Children.

BACKGROUND: Children constitute an important component of the influenza burden and community transmission, but the frequency of asymptomatic infection and post-influenza sequelae at the community level is poorly understood. METHODS: Two community-based prospective cohort studies (2011-2020, 2017-2020) and 1 case-ascertained study (2012-2017) were conducted in Managua, Nicaragua. Non-immunocompromised children aged 0-14 years with ≥1 influenza infections, determined by polymerase chain reaction and hemagglutination inhibition assay, were included. RESULTS: A total of 1272 influenza infections occurred in the household-based portion of the study. Influenza infection was asymptomatic in 84 (6.6%) infections, and the asymptomatic fraction increased with age (1.7%, 3.5%, and 9.1% for ages 0-1, 2-4, and 5-14, respectively; P < .001). Of asymptomatic children, 43 (51.2%) shed virus, compared to 1099 (92.5%) symptomatic children (P < .001). Also, 2140 cases of influenza occurred in the primary care portion of the study. Sequelae of influenza were rare, with the most common being pneumonia (52, 2.4%) and acute otitis media (71, 3.3%). A/H1N1 had higher age-adjusted odds of acute otitis media (odds ratio [OR] 1.99, 95% confidence interval [CI]: 1.14-3.48; P = .015) and hospitalization (OR 3.73, 95% CI: 1.68-8.67; P = .002) than A/H3N2. B/Victoria had higher age-adjusted odds of pneumonia (OR 10.99, 95% CI: 1.34-90.28; P = .026) than B/Yamagata. CONCLUSIONS: Asymptomatic influenza infection is much less common in children than adults, although viral shedding still occurs in asymptomatic children. Post-influenza sequelae are rare in children in the community setting, and virus strain may be important in understanding the risk of sequelae.

Pediatric burden and seasonality of human metapneumovirus over 5 years in Managua, Nicaragua.

BACKGROUND: Human metapneumovirus (hMPV) is an important cause of pediatric respiratory infection. We leveraged the Nicaraguan Pediatric Influenza Cohort Study (NPICS) to assess the burden and seasonality of symptomatic hMPV infection in children. METHODS: NPICS is an ongoing prospective study of children in Managua, Nicaragua. We assessed children for hMPV infection via real-time reverse-transcription polymerase chain reaction (RT-PCR). We used classical additive decomposition analysis to assess the temporal trends, and generalized growth models (GGMs) were used to estimate effective reproduction numbers. RESULTS: From 2011 to 2016, there were 564 hMPV symptomatic infections, yielding an incidence rate of 5.74 cases per 100 person-years (95% CI 5.3, 6.2). Children experienced 3509 acute lower respiratory infections (ALRIs), of which 160 (4.6%) were associated with hMPV infection. Children under the age of one had 55% of all symptomatic hMPV infections (62/112) develop into hMPV-associated ALRIs and were five times as likely as children over one to have an hMPV-associated ALRI (rate ratio 5.5 95% CI 4.1, 7.4 p < 0.001). Additionally, symptomatic reinfection with hMPV was common. In total, 87 (15%) of all observed symptomatic infections were detected reinfections. The seasonality of symptomatic hMPV outbreaks varied considerably. From 2011 to 2016, four epidemic periods were observed, following a biennial seasonal pattern. The mean ascending phase of the epidemic periods were 7.7 weeks, with an overall mean estimated reproductive number of 1.2 (95% CI 1.1, 1.4). CONCLUSIONS: Symptomatic hMPV infection was associated with substantial burden among children in the first year of life. Timing and frequency of symptomatic hMPV incidence followed biennial patterns.

Distinct promoter regions of the oxytocin receptor gene are hypomethylated in Prader-Willi syndrome and in Prader-Willi syndrome associated psychosis.

Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder caused by a loss of usually paternally expressed, maternally imprinted genes located on chromosome 15q11-q13. Individuals with PWS display a specific behavioral phenotype and have a higher susceptibility than the general population for certain psychiatric conditions, especially psychosis. An impairment of the oxytocin system has been described in Prader-Willi syndrome, but has not yet been investigated in detail on the epigenetic level. Recent studies have pointed out altered methylation patterns of the oxytocin receptor gene (OXTR) in various psychiatric disorders, including psychosis. In this study, we investigated methylation rates of CpG dinucleotides in the promoter region of the oxytocin receptor gene via bisulfite-sequencing using DNA extracted from peripheral blood samples of 31 individuals with PWS and 14 controls matched for age, sex, and BMI. Individuals with PWS show significantly lower methylation in the intron 1 region of the OXTR than neurotypical controls (p = 0.012). Furthermore, male PWS subjects with psychosis show significantly lower methylation of the OXTR exon 1 region than those without psychosis (p = 0.002). Transcription factor binding site analysis revealed E2F1 as a transcription factor potentially binding to the exon 1 region. E2F1 is physiologically regulated by Necdin, an anti-apoptotic protein whose corresponding gene is located within the PWS locus. This study provides evidence of a disruption of the Oxytocin system on an epigenetic level in PWS in general and in individuals with PWS and psychosis.

Association of SARS-CoV-2 Seropositivity and Symptomatic Reinfection in Children in Nicaragua.

Importance: The impact of the SARS-CoV-2 pandemic on children remains unclear. Better understanding of the burden of COVID-19 among children and their risk of reinfection is crucial, as they will be among the last groups vaccinated. Objective: To characterize the burden of COVID-19 and assess how risk of symptomatic reinfection may vary by age among children. Design, Setting, and Participants: In this prospective, community-based pediatric cohort study conducted from March 1, 2020, to October 15, 2021, 1964 nonimmunocompromised children aged 0 to 14 years were enrolled by random selection from the Nicaraguan Pediatric Influenza Cohort, a community-based cohort in District 2 of Managua, Nicaragua. Additional newborn infants aged 4 weeks or younger were randomly selected and enrolled monthly via home visits. Exposures: Prior COVID-19 infection as confirmed by positive anti-SARS-CoV-2 antibodies (receptor binding domain and spike protein) or real-time reverse transcriptase-polymerase chain reaction (RT-PCR)-confirmed COVID-19 infection at least 60 days before current COVID-19 infection. Main Outcomes and Measures: Symptomatic COVID-19 cases confirmed by real-time RT-PCR and hospitalization within 28 days of symptom onset of a confirmed COVID-19 case. Results: This cohort study assessed 1964 children (mean [SD] age, 6.9 [4.4] years; 985 [50.2%] male). Of 1824 children who were tested, 908 (49.8%; 95% CI, 47.5%-52.1%) were seropositive during the study. There were also 207 PCR-confirmed COVID-19 cases, 12 (5.8%) of which were severe enough to require hospitalization. Incidence of COVID-19 was highest among children younger than 2 years (16.1 cases per 100 person-years; 95% CI, 12.5-20.5 cases per 100 person-years), which was approximately 3 times the incidence rate in any other child age group assessed. In addition, 41 symptomatic SARS-CoV-2 episodes (19.8%; 95% CI, 14.4%-25.2%) were reinfections. Conclusions and Relevance: In this prospective, community-based pediatric cohort study, rates of symptomatic and severe COVID-19 were highest among the youngest participants, with rates stabilizing at approximately 5 years of age. In addition, symptomatic reinfections represented a large proportion of symptomatic COVID-19 cases.